Cryptococcus neoformans var. grubii H99
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ABSTRACT:
PROVIDER: PRJNA175664 | ENA |
REPOSITORIES: ENA
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Project description:TLR activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades within the first hours after stimulation. Whether concurrent changes in the cellular metabolism that occur upon TLR activation influence the quality of the transcriptional responses remain unknown. Here we investigated how macrophages adopt their metabolism early after activation to regulate TLR-inducible gene induction. Macrophages increase glucose metabolism and adopt fluxes through the TCA cycle to foster Citrate synthesis. We concomitantly observe activation of ATP-Citrate Lyase (Acly), resulting in augmented acetyl-CoA synthesis and histone acetylation. To investigate which genes and genes classes require ATP-citrate lyase activity for induction we stimulated bone marrow derived macrophages with LPS after ATP-citrate lyase inhibition.
2019-12-16 | GSE129497 | GEO
Project description:Acetyl-Coenzyme A (acetyl-CoA) is a central metabolite and the acetyl source for protein acetylation, particularly histone acetylation that promotes gene expression. However, the effect of acetyl-CoA levels on histone acetylation status in plants remains unknown. Here, we show that malfunctioned cytosolic acetyl-CoA carboxylase1 (ACC1) in Arabidopsis leads to elevated levels of acetyl-CoA and promotes histone hyperacetylation predominantly at lysine 27 of histone H3 (H3K27). The increase of H3K27 acetylation (H3K27ac) is dependent on ATP-citrate lyase which cleaves citrate to acetyl-CoA in the cytoplasm, and requires histone acetyltransferase GCN5. A comprehensive analysis of the transcriptome and metabolome in combination with the genome-wide H3K27ac profiles of acc1 mutants, demonstrate the dynamic changes of H3K27ac, gene transcripts and metabolites occurring in the cell by the increased levels of acetyl-CoA. This study suggests that H3K27ac is an important link between cytosolic acetyl-CoA level and gene expression in response to the dynamic metabolic environments in plants.
2017-09-25 | GSE79524 | GEO
Project description:The interaction of Cryptococcus neoformans with phagocytic cells of the innate immune system is a key step in disseminated disease leading to meningoencephalitis in immunocompromised individuals. Transcriptional profiling of cryptococcal cells harvested from cell culture medium or from macrophages found differential expression of metabolic and other functions during fungal adaptation to the intracellular environment by SAGE analysis. We focused on the ACL1 gene for ATP-citrate lyase, which converts citrate to acetyl-CoA, because this gene showed elevated transcript levels in macrophages and because of the importance of acetyl-CoA as a central metabolite. Mutants lacking ACL1 showed delayed growth on medium containing glucose, reduced cellular levels of acetyl-CoA, defective production of virulence factors, increased susceptibility to the antifungal drug fluconazole and decreased survival within macrophages. Importantly, acl1 mutants were unabl e to cause disease in a murine inhalation model, a phenotype that was more extreme than other mutants with defects in acetyl-CoA production (e.g., an acetyl-CoA synthetase mutant). Loss of virulence is likely due to perturbation of critical physiological interconnections between virulence factor expression and metabolism in C. neoformans. Phylogenetic analysis and structural modeling of cryptococcal Acl1 identified three indels unique to fungal protein sequences; these differences may provide opportunities for the development of pathogen-specific inhibitors. SAGE analysis of C. neoformans cells isolated from macrophages The murine macrophage-like cell line J774A.1 was maintained at 37°C in 10% CO2 in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% heat-inactivated fetal calf serum (FBS), 1% nonessential amino acids, 100 µg mL-1 penicillin-streptomycin, and 4 mM L-glutamine (Invitrogen). Cryptococcus cells were opsonized with monoclonal antibody 18B7 against capsule (1 µg mL-1), and macrophages were treated with recombinant mouse gamma interferon (IFN-gamma) (50 U mL-1) and lipopolysaccharide (LPS) (0.3 µg mL-1) prior to co-incubation at a multiplicity of infection (MOI) of 1:1. Macrophages were inoculated with H99 cells and washed after 1 h of inoculation to remove unattached, extracellular fungal cells. After 6 h of incubation, sterile, ice-cold distilled H2O was applied to each well to lyse the macrophages, and the fungal cells (4 x 107) were harvested by centrifugation. H99 control cells were prepared by growth under the same condition but without macrophages, and 108 cell s were harvested.
2013-08-15 | GSE41066 | GEO
Project description:Metabolic production of acetyl-CoA has been linked to histone acetylation and gene regulation, however the mechanisms are largely unknown. We show that the metabolic enzyme acetyl-CoA synthetase 2 (ACSS2) is a critical and direct regulator of histone acetylation in neurons and of long-term mammalian memory. We observe increased nuclear ACSS2 in differentiating neurons in vitro. Genome-wide, ACSS2 binding corresponds with increased histone acetylation and gene expression of key neuronal genes. These data indicate that ACSS2 functions as a chromatin-bound co-activator to increase local concentrations of acetyl-CoA and to locally promote histone acetylation for transcription of neuron-specific genes. Remarkably, in vivo attenuation of hippocampal ACSS2 expression in adult mice impairs long-term spatial memory, a cognitive process reliant on histone acetylation. ACSS2 reduction in hippocampus also leads to a defect in upregulation of key neuronal genes involved in memory. These results reveal a unique connection between cellular metabolism and neural plasticity, and establish a link between generation of acetyl-CoA and neuronal chromatin regulation. Global survey of gene expression in CAD cells and differentiated CAD neurons following lentiviral knockdown of ACSS2 or ATP citrate lyase (ACL) (and control = scramble hairpin); survey of hippocampal gene expression changes associated with retrieval of fear memory, after ACSS2-AAV knockdown or in EGFP-AAV control (comparison of 0h vs. 1h post-memory retrieval).
2017-05-01 | E-GEOD-76853 | biostudies-arrayexpress
Project description:Acetyl-CoA is a key metabolite in all organisms, implicated in transcriptional regulation, post-translational modification as well as fuelling the TCA cycle and the synthesis and elongation of fatty acids. The obligate intracellular parasite Toxoplasma gondii possesses two enzymes which produce acetyl-CoA in the cytosol and nucleus: the acetyl-CoA synthase (ACS) and the ATP-citrate lyase (ACL), while the branched chain α-ketoacid dehydrogenase (BCKDH) generates acetyl-CoA in the mitochondrion. Given the diverse functions of acetyl-CoA, we know little about the specific roles of distinct sub-cellular acetyl-CoA pools and how these impact overall parasite physiology. To assess the broad functions of nucleo-cytosolic as well as mitochondrial acetyl-CoA, we analysed the acetylome and total proteome of parasites lacking ACL/ACS or BCKDH.
2020-05-07 | PXD016133 | Pride
Project description:Ne-lysine acetylation within the lumen of the endoplasmic reticulum (ER) is a recently characterized protein quality control system that positively selects properly folded glycoproteins in the early secretory pathway. Overexpression of the ER acetyl-CoA transporter AT-1 in mouse forebrain neurons results in increased dendritic branching, spine formation, and an autistic-like phenotype that is attributed to altered glycoprotein flux through the secretory pathway. AT-1 overexpressing neurons maintain the cytosolic pool of acetyl-CoA by upregulation of SLC25A1, the mitochondrial citrate/malate antiporter, and ATP citrate lyase (ACLY), which converts cytosolic citrate into acetyl-CoA. All three genes have been associated with autism spectrum disorder (ASD), suggesting that aberrant cytosolic to ER flux of acetyl-CoA can be a mechanistic driver for the development of ASD. We therefore generated a SLC25A1 neuron transgenic (nTg) mouse, which displayed autistic-like behaviors with a jumping stereotypy. The mice exhibited increased steady-state levels of citrate and acetyl-CoA, disrupted white matter integrity with activated microglia, and altered synaptic plasticity and morphology. Finally, acetylomic and proteomic analysis revealed differential adaptations in the hippocampus and cortex. Overall, our study reinforces the connection between aberrant cytosol-to-ER flux of acetyl-CoA flux and the development of an autistic-like phenotype.
2022-02-26 | PXD025415 | Pride
Project description:Endoplasmic-reticulum (ER)-based N-lysine acetylation is a positive selection marker for properly folded glycoproteins in the early secretory pathway, serving as an important protein quality control system. Excessive N-lysine acetylation within the ER via overexpression of the acetyl-CoA transporter AT-1 results in altered glycoprotein flux through the secretory pathway, which dramatically impacts dendritic branching and spine formation causing an autistic-like phenotype in the mouse. AT-1 works in concert with SLC25A1, the citrate/malate antiporter in the mitochondria, SLC13A5, the plasma membrane sodium/citrate synporter, and ATP citrate lyase (ACLY), the cytosolic enzyme that converts citrate into acetyl-CoA, in order to maintain the cytosolic-to-ER flux of acetyl-CoA. As such, we generated the SLC13A5 neuron transgenic (nTg) mouse with the hypothesis that increasing cytosolic citrate would impact acetyl-CoA flux into the ER and recapitulate the autistic-like AT-1 nTg model. Here, we demonstrated the SLC13A5 nTg mouse exhibits autistic-like behaviors with a jumping stereotypy. The mice displayed disrupted white matter integrity and altered synaptic structure and function. Finally, analysis of both the proteome and acetylome revealed unique adaptations in the hippocampus and cortex to SLC13A5 overexpression, implicating the importance of metabolic consequences of altered cytosolic citrate/acetyl-CoA availability in the neuron. Overall, our results corroborate the mechanistic link between aberrant intracellular citrate/acetyl-CoA flux and the development of an autistic-like phenotype.
2021-08-26 | PXD026624 | Pride
Project description:Old age is associated with a progressive decline of mitochondrial function and changes in nuclear chromatin. However, little is known about how metabolic activity and epigenetic modifications change as organisms reach their midlife. Here, we assessed how protein acetylation changes during midlife in Drosophila melanogaster. Midlife flies show elevated acetyl-CoA levels and alterations in protein acetylation. Based on these observations, we decreased the activity of the acetyl-CoA-synthesizing enzyme ATP citrate lyase (ATPCL). We find that lower ATPCL activity alleviates the observed aging-associated changes and promote longevity. Our findings reveal a pathway that couples changes of intermediate metabolism during aging with the chromatin-mediated regulation of transcription and changes in the activity of associated enzymes that modulate organismal lifespan.
2016-01-22 | PXD003318 | Pride
Project description:Cytosolic acetyl-coenzyme A is a precursor for many biotechnologically relevant compounds produced by Saccharomyces cerevisiae. In this yeast, cytosolic acetyl-CoA synthesis and growth strictly depend on expression of either the Acs1 or Acs2 isoenzyme of acetyl-CoA synthetase (ACS). Since hydrolysis of ATP to AMP and pyrophosphate in the ACS reaction constrains maximum yields of acetyl-CoA-derived products, this study explores replacement of ACS by two ATP-independent pathways for acetyl-CoA synthesis. After evaluating expression of different bacterial genes encoding acetylating acetaldehyde dehydrogenase (A-ALD) and pyruvate-formate lyase (PFL), acs1M-NM-^T acs2M-NM-^T S. cerevisiae strains were constructed in which A-ALD or PFL successfully replaced ACS. In A-ALD-dependent strains, aerobic growth rates of up to 0.27 h-1 were observed, while anaerobic growth rates of PFL-dependent S. cerevisiae (0.21 h-1) were stoichiometrically coupled to formate production. In glucose-limited chemostat cultures, intracellular metabolite analysis did not reveal major differences between A-ALD-dependent and reference strains. However, biomass yields on glucose of A-ALD- and PFL-dependent strains were lower than those of the reference strain. Transcriptome analysis suggested that reduced biomass yields were caused by acetaldehyde and formate in A-ALD- and PFL-dependent strains, respectively. Transcript profiles also indicated that a previously proposed role of Acs2 in histone acetylation is probably linked to cytosolic acetyl-CoA levels rather than to direct involvement of Acs2 in histone acetylation. While, for the first time, demonstrating that yeast ACS can be fully replaced by alternative reactions, this study demonstrates that further modifications are needed to achieve optimal in vivo efficiencies of the supply of acetyl-CoA as product precursor. To investigate the impact of introduced changes in native pathway of cytosolic acetyl-CoA formation in S. cerevisiae, a DNA microarray-based transcriptome analysis was performed on aerobic or anaerobic, glucose-limited chemostat cultures.
2013-11-21 | E-GEOD-47983 | biostudies-arrayexpress
Project description:The virulence factor HlyA of Uropathogenic Escherichia coli (UPEC) could modulate host cell metabolism and inhibits NF-κB signaling pathway. However, whether there is a link between these two processes remains elusive. Here, we demonstrated UPEC could suppress metabolic enzyme ATP citrate lyase (ACLY) that resulted into histone deacetylation by decreasing the levels of acetyl-CoA. The level of histone acetylation was rescued supplementation of acetate. Furthermore, using H3 Lysine9 acetylation (H3K9ac) immunoprecipitation coupled next generation sequencing (ChIP-seq), we found that UPEC cause site specific regulation of H3K9ac which correlates with the expression of pro-inflammatory cytokines and chemokines. To be more specific, the expression of pro-inflammatory cytokines and chemokines like IL 8, CXCL2, and IL-1α are suppressed by UPEC mediated decreasing of H3K9ac at TSS-promoter region. Thus, this study established that UPEC manipulate host cell metabolism to impact histone acetylation at specific loci, correlating with cytokines and chemokines expression, as a means to inhibit NF-κB signaling.
2019-05-22 | GSE131560 | GEO